Attenuation of muscle atrophy in a murine model of cachexia by inhibition of the dsRNA-dependent protein kinase

H. Eley, S.T. Russell, M.J. Tisdale*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Atrophy of skeletal muscle is due to a depression in protein synthesis and an increase in degradation. Studies in vitro have suggested that activation of the dsRNA-dependent protein kinase (PKR) may be responsible for these changes in protein synthesis and degradation. In order to evaluate whether this is also applicable to cancer cachexia the action of a PKR inhibitor on the development of cachexia has been studied in mice bearing the MAC16 tumour. Treatment of animals with the PKR inhibitor (5 mg kg-1) significantly reduced levels of phospho-PKR in muscle down to that found in non-tumour-bearing mice, and effectively attenuated the depression of body weight, with increased muscle mass, and also inhibited tumour growth. There was an increase in protein synthesis in skeletal muscle, which paralleled a decrease in eukaryotic initiation factor 2α phosphorylation. Protein degradation rates in skeletal muscle were also significantly decreased, as was proteasome activity levels and expression. Myosin levels were increased up to values found in non-tumour-bearing animals. Proteasome expression correlated with a decreased nuclear accumulation of nuclear factor-κB (NF-κB). The PKR inhibitor also significantly inhibited tumour growth, although this appeared to be a separate event from the effect on muscle wasting. These results suggest that inhibition of the autophosphorylation of PKR may represent an appropriate target for the attenuation of muscle atrophy in cancer cachexia. © 2007 Cancer Research UK.

Original languageEnglish
Pages (from-to)1216-1222
Number of pages7
JournalBritish Journal of Cancer
Volume96
Issue number8
DOIs
Publication statusPublished - 27 Mar 2007

Fingerprint

Cachexia
Muscular Atrophy
Protein Kinases
Neoplasms
Skeletal Muscle
Proteasome Endopeptidase Complex
Muscles
Proteolysis
Eukaryotic Initiation Factor-2
eIF-2 Kinase
Myosins
Growth
Atrophy
Proteins
Body Weight
Phosphorylation
Research

Bibliographical note

© 2007 Cancer Research UK Creative Commons Attribution-NonCommercial-Share-Alike 3.0 licence, subject to the conditions listed at http://creativecommons.org/licences/by-nc-sa/3.0/

Keywords

  • cancer cachexia
  • dsRNA-dependent protein kinase
  • inhibition
  • muscle protein degradation
  • muscle protein synthesis

Cite this

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title = "Attenuation of muscle atrophy in a murine model of cachexia by inhibition of the dsRNA-dependent protein kinase",
abstract = "Atrophy of skeletal muscle is due to a depression in protein synthesis and an increase in degradation. Studies in vitro have suggested that activation of the dsRNA-dependent protein kinase (PKR) may be responsible for these changes in protein synthesis and degradation. In order to evaluate whether this is also applicable to cancer cachexia the action of a PKR inhibitor on the development of cachexia has been studied in mice bearing the MAC16 tumour. Treatment of animals with the PKR inhibitor (5 mg kg-1) significantly reduced levels of phospho-PKR in muscle down to that found in non-tumour-bearing mice, and effectively attenuated the depression of body weight, with increased muscle mass, and also inhibited tumour growth. There was an increase in protein synthesis in skeletal muscle, which paralleled a decrease in eukaryotic initiation factor 2α phosphorylation. Protein degradation rates in skeletal muscle were also significantly decreased, as was proteasome activity levels and expression. Myosin levels were increased up to values found in non-tumour-bearing animals. Proteasome expression correlated with a decreased nuclear accumulation of nuclear factor-κB (NF-κB). The PKR inhibitor also significantly inhibited tumour growth, although this appeared to be a separate event from the effect on muscle wasting. These results suggest that inhibition of the autophosphorylation of PKR may represent an appropriate target for the attenuation of muscle atrophy in cancer cachexia. {\circledC} 2007 Cancer Research UK.",
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Attenuation of muscle atrophy in a murine model of cachexia by inhibition of the dsRNA-dependent protein kinase. / Eley, H.; Russell, S.T.; Tisdale, M.J.

In: British Journal of Cancer, Vol. 96, No. 8, 27.03.2007, p. 1216-1222.

Research output: Contribution to journalArticle

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